p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase

By P. Jiang, W. Du, Xing-wu Wang, A. Mancuso, Xiangxi Gao, Mian Wu, Xiaolu Yang. Nature Cell Biology, 2011

734 citations recorded by the source corpus.

Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen. This metabolic signature (aerobic glycolysis or the Warburg effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3dbd0d46ea5b707bbec00012bc906385a7819d81

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. David M. Sabatini
2. Huayan Duan
3. Karen H. Vousden
4. Eyal Gottlieb
5. Huafeng Zhang
6. Zhaoyong Li
7. Yuanyuan An
8. J. Cantor

In Molecular Biology

1. J. Cantor
2. David M. Sabatini
3. Eyal Gottlieb
4. M. Guo
5. Haolan Wang
6. Yongheng Chen
7. Hudie Wei
8. Huayan Duan

In Oncology

1. David M. Sabatini
2. M. Guo
3. Haolan Wang
4. Yongheng Chen
5. Hudie Wei
6. Karen H. Vousden
7. Eyal Gottlieb
8. Huafeng Zhang

Citations in the corpus

• Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “95,96 p53 inhibits glucose uptake and glycolysis by suppressing the expression and translocation of glucose transporter proteins such as GLUT1 and GLUT4.”
• The role of m6A RNA methylation in cancer metabolism (2022, background): “In addition, p53 inhibits glucose consumption and NADPH expression by binding with G6PD [72].”
• Glucose-6-Phosphate Dehydrogenase, NADPH, and Cell Survival (2012, background): “A signal downstream of the tumor suppressor p53, called TIGAR (TP53induced glycolysis and apoptosis regulator) has been reported to be a positive regulator of G6PD (21).”
• Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Indeed, p53-deficient cells exhibited an elevated flux of glucose into the ox-PPP, along with increases in both NADPH levels and lipogenic rates, relative to cells expressing wild-type p53 (68).”
• Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “The tumour suppressor p53 protein inhibits the PPP by directly binding to G6PD and preventing the formation of the active dimer [59].”
• Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells (2012, background): “Labelled serine (M13, mass isotopomer with 3 (13)C incorporated) and unlabelled serine (M10, mass isotopomer with 0 (13)C incorporated) is shown in cells grown in complete (Com) or serine- and glycinedeficient (2) medium for the indicated times.”